Sickle cell disease (SCD) is a chronic disease characterized by painful episodes, increased morbidity and mortality and has many unmet needs in effective treatment. While the pathophysiology of SCD is complex, hemolysis, red blood cell (RBC) vascular adhesion and an altered redox state all play key roles. Prior studies from our group support the hypothesis that the drug N-acetylcysteine (NAC) can modulate SCD by cleaving hyperactive von Willebrand factor, a vascular adhesion protein. In an ongoing study of NAC infusions in stable outpatients with SCD, we have found an effect on VWF, as well as an increase in the antioxidant activity in whole blood, plasma and red blood cells (RBC) and a decrease in RBC fragments and dense cells, among other findings. The drug has been well tolerated by subjects enrolled to date. We further hypothesize that NAC will be an effective treatment for SCD vaso-occlusive crisis (VOC) by decreasing VWF adhesiveness and improving red blood cell function and viability. To obtain the data needed to develop a successful multicenter randomized placebo controlled trial of NAC in VOC, we propose the following Specific Aims: 1) To conduct a pilot study of NAC in patients presenting to the University of Washington Medical Center emergency room or inpatient unit in VOC, with NAC infusions continuing for 5 days or until discharge. Endpoints for this pilot study will be feasibility, safet, and measures of clinical efficacy. 2) To assess research laboratory correlates of NAC activity in this setting, including measures of VWF activity, VWF multimer composition, RBC fragments and dense cells, cellular aggregates, and measures reflective of antioxidant activity. This will increase our understanding of the mechanism(s) of NAC in treatment of SCD and inform the selection of laboratory biomarkers for the multicenter trial. And, 3) To develop a multicenter randomized placebo-controlled clinical trial of NAC in SCD vaso-occlusive crisis, with clinical response and laboratory endpoints chosen based on findings from this pilot trial and with engagement of sickle cell medical providers/investigators across the country. NAC is a promising, low cost therapy for VOC which could provide benefit for many patients with sickle cell disease.